Dyskinesias are hyperkinetic involuntary movements, which are often present as discrete episodic attacks or paroxysms. They share similarities with other paroxysmal neurologic disorders, such as epilepsy and migraine. They occur in sporadic and familial forms, are precipitated by various stimuli (e.g. stress, fatigue, menses, alcohol, caffeine), and frequently respond to anticonvulsant medications. Dyskinesias are further categorized into kinesigenic (movement-induced) and non-kinesigenic (spontaneous) forms. We have genetically mapped a locus associated with a non-kinesigenic form of familial paroxysmal dyskinesia (FPD) to chromosome 2q (FPD1) and a kinesigenic form to chromosome 16 (FPD2). Furthermore, we have identified other families not linked to either locus, demonstrating further genetic heterogeneity. We plan to identify and characterize genes, and mutations responsible for familial paroxysmal dyskinesias. Families in whom the disorder is not linked to FPD1 or FPD2 will be studied using a general genetic linkage approach to identify additional FPD loci. We will perform mutation analysis on candidate genes linked to FPD loci. A variety of positional cloning strategies will be utilized if candidate gene analysis is unsuccessful. Identification of FPD genes, coupled with extensive clinical data, will allow us to characterize the spectrum of phenotypes caused by mutations in a single gene and to compare phenotypes of patients with mutations at different loci. Of particular interest will be whether there is a correlation between specific genes and mutations with therapeutic responses, and the prominent but diverse effects that such neuroactive agents as alcohol and caffeine have on these disorders. Molecular characterization of the FPDs will lead to a new genetic classification and a better understanding of these disorders. Characterization of the pathogenic mechanisms underlying the FPDs will lead to improved diagnosis, may suggest novel therapeutic strategies, and will shed light on more complex paroxysmal disorders, such as migraine and epilepsy.